IE850241L

IE850241L - FURO (3,4-c) PYRIDINE DERIVATIVES

Info

Publication number: IE850241L
Application number: IE850241A
Authority: IE
Original assignee: Sod Conseils Rech Applic
Priority date: 1984-02-02
Filing date: 1985-02-01
Publication date: 1985-08-02
Also published as: FR2559062B1; BE901545A; FI82051B; LU85744A1; MA20342A1; FR2559152A1; OA07947A; FI850275A0; PT79913B; ATA27585A; US4581362A; DK158951C; ZA85508B; NO160369B; NO160369C; SE8500460D0; SE8500460L; IE58229B1; GB8402740D0; SE460903B

Abstract

This invention relates to new 1,3-dihydro-6-(1-hydroxy-2-dimethylaminomethyl-allyl)-7-hydroxy-furo-( 3,4-c)-pyridine derivatives of the general formula: <IMAGE> wherein, each of A1 and A2 independently, represents various substituents, to a process for the preparation of these compounds comprising reacting a 6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine derivative of the general formula II <IMAGE> II with 1-dimethylaminomethyl-vinylmagnesium bromide at the boil, in a non polar solvent and hydrolyzing the 7-benzyloxy group and to a therapeutic composition of matter, comprising as an essential ingredient therein, at least one of these compounds. The compounds according to the invention are of interest for their therapeutic activity, principally as anti-depressive agents. [US4581362A]

Description

58229 This invention relates to new 6-(l-hydroxy-2-dimethyl-amino-methyl-allyl)-furo-(3,4-c)-pyr id ine derivatives, to a process for their preparation and to therapeutic compositions containing them.

The invention provides 1,3-dihydro-6-(l-hydroxy-2-d imethylaminomethyl-allyl)-7-hydroxy-furo - (3,4-c) - pyridine derivatives of the general formula : H3C N— H3C wherein, each of A^ and A2 independently, represents a hydrogen atom, a straight .chain saturated or unsaturated 10 hydrocarbon group having from 1 to 5 carbon atoms, a heterocyclic group having up to 6 ring atoms, a carbornonocyclic group, a phenylalkyl group or a phenylalkeny 1 group, each of the groups represented by A^ and A2 being unsubstituted or being substituted by one or more chlorine or 15 fluorine atoms, trifluoromethyl groups, alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms, alkylthio groups having from 1 to 5 carbon atoms, dialkylamino groups in which each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups in which each 20 of the two alkyl groups and the alkoxy groups has from 1 to 5 carbon atoms or a or g - (N-pyrro1idiny'|J-alko*y groups in which the alkoxy group has from 1 to 5 carbon atoms ; and further provides pharmaceutically acceptable salts of such compounds.

The compounds according to the invention are of interest for their therapeutical activity, principally as antidepressive agents. 5 The invention also provides a process for the preparation of the said compounds, the process comprising reacting a 6- formyl - 7- benzyloxy -furo - (3,4-c) - pyridine derivative of the general formula II 0 10 wherein A^ and A^ have the above meanings with 1-dimethyl-aminomethyl-vinylmagnesium bromide at the boil, in a non polar solvent such as tetrahydrofuran and hydrolysing the 7-benzyloxy group of the resultant intermediate by treatment with an acid. 15 To obtain the 6-formyl-7-benzyloxy-furo-(3,4-c)- pyridine derivative II the starting material is the compound III : obtained by the method described in our patent application 20 No. 288/82 submitted to the following sequence of reactions : - 3 - The invention further provides a therapeutical composition comprising a 1,3-dihydro-6-(l-hydroxy-2-dimethyl-amino-methyl-allyl)-furo-(3,4-c)-pyridine derivative of the general formula I as above defined or a pharmaceutically 5 acceptable salt thereof in admixture with a therapeutically acceptable diluent or carrier.

The following examples illustrate the invention.

Example 1 1, 3-d ihydro-3-methy1-6-(l-hydroxy-2-d imethylaminomethyl-allyl)-10 7-hy_droxy-f uro- (3, 4-c) -pyr idine a) Preparation of the organomagnesium reagent In a two litre reactor fitted with warming, cooling and stirring means were poured, under nitrogen circulation, 19.4 g (0.8 mol) of magnesium, and 100 ml of tetrahydrof uran, 15 preferably distilled on lithium aluminium hydride. The mixture was refluxed.

There was then slowly added 132 g (0.8 mol) of 3-dimethylamino-2-bromo-l-propylene. No external heating was applied, the reflux being maintained and controlled by the 20 addition of this compound. At the end of the addition, one litre of distilled tetrahydrofuran was added. The mixture was refluxed for two hours and then cooled to 10°C. b) Reaction To the reaction mixture from the previous step was 25 slowly added, under stirring, 107.6 g (0.4 mol) of 1,3 -dihydro- 3-methyl- 6-formyl- 7-benzyloxy- furo- (3,4-c) -pyridine. The temperature reached about 25°C at the end of the addition. Stirring was maintained overnight at room temperature. The mixture was then cooled to 0°C and 250 ml of 30 water saturated with ammonium chloride and 250 ml of diethyl - 5 - ether were added to it. After stirring for 15 minutes at room temperature there was obtained a two-phase mixture with an oil supernatant.

The mixture was separated and the aqueous phase was 5 extracted twice with 250 ml aliquots of diethyl ether. The extracts were added to the oily phase, which had been washed with water three times. The oily phase was then dried on magnesium sulphate, treated with carbon black, concentrated to dryness and extracted twice with 250 ml of diisopropylether. 10 The extracts were filtered, concentrated (reduction to 1/4 of initial volume) and cooled overnight, leading to a precipitate, which was separated and washed with diisopropylether. Yield 104 g (73 %) . c) Debenzylat i on 15 Into the above reactor were poured the product of the previous step and 700 ml of hydrochloric acid. The mixture was stirred, warmed to 55°C, maintained at that temperature for three hours, and then cooled to 0°C. After addition of water, neutralisation with sodium hydroxide and saturation with 20 souium culorioe, the mixture wad extructeu three times with 500 ml aliquots of chloroform. The extracts were washed with water, dried on magnesium sulphate, filtered and evaporated to dryness. The residue was recrystallized from methanol. Yield 90.5 g (92 %) of a product melting at 200-205°C (Tottoli) , 25 with decomposition, the analysis of which showed a good correspondence with the formula cj4H2oN2°3' 2HC1* The overall yield was 67 %.

The preparation of the other compounds of the invention follows the same process except that, in step (b), the 30 starting material is different ; the following examples will, accordingly refer to example 1 and only mention the new starting material, the overall yield and the characteristics of the compound obtained. - 6 - Example 2 1,3-dihydro-3-propyl-6-(l-hydroxy-2-d imethylaminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-pyr idine The method of example 1 was repeated, but starting with 5 119 g (0.4 mol) of l,3-dihydro-3-propyl-6-formyl-7-benzyloxy- furo-(3,4-c)-pyridine. Yield 89 g (61 %) of a product melting at 187-194°C (Tottoli), with decomposition, the analysis of which showed a good correspondence with the formula C16H24N2°3' 2HC1" 10 Example 3 l,3-dihydro-3-cyclohexyl-6-(1-hydroxy-2-d imethylaminomethyl-allyl) -7-hydroxy-furo-(3,4-c)-pyridine The method of example 1 was repeated, but starting with 135 g (0.4 mol) of 1,3-dihydro-3-cyclohexyl-6-formyl-7-15 benzyloxy-furo-(3,4-c)-pyridine. Yield 92 g (57 %) of a product melting at 180-184°C (Tottoli), with decomposition, the analysis of which showed a good correspondence with the formula ci9H28N2°3' 2HC1* Ex ample 4 20 1_, 3-d ihydro-3-pheny 1 -6- (1-J\ydroxy-2-d imethy 1 a mi nomethyl-allyl) -7-hydroxy-furo- (3, 4_^c) -pyr idine The method of example 1 was repeated, but starting with 135 g (0.4 mol) of 1,3-dihydro-3-phenyl-6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine. Yield 77 g (48 %) of a 25 product melting at 210-215°C (Tottoli), with decomposition, the analysis of which showed a good correspondence with the formula C^9H22N2°3' 2HC-1" Example 5 1/ 3-d ihydro-3-p-chlorophenyl-6- (1-hydroxy-2-d imj?thylaminomethyl-30 a_lly 1J-7-hydroxy-furo- (3,4-c) -pyridine - 7 - The method of example 1 was repeated, but starting with 146 g (0.4 mol) of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-benzyloxy -furo-(3,4-c)-pyridine. Yield 95 g (55 %) of a product melting at 195-200°C (Tottoli), with decomposition, the 5 analysis of which showed a good correspondence with the. formula • 2HC1.

Example 6 1,3-d ihydro-3-(2,3-d ichlorophenyl)-6-(1-hydroxy-2-dimethy1-ami nomethy1-allyl)-7~hydroxy-furo-(3,4-c)-pyr id ine 10 The method of example 1 was repeated, but starting with 160 g (0.4 mol) of 1,3-dihydro-3-(2,3-dichloro-phenyl)-6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine. Yield 82 g (44 %) of a product melting at 180-184°C (Tottoli), with decomposition, the analysis of which showed a good 15 correspondence with the formula C^gH^Cl2N2°3* 2HC1.

Example 7 1,3-d ihydro-3-p-fluorophenyl-6-(1-hydroxy-2-d imethylaminomethyl-allyl) -7-hydroxy-furo-(3,4-c)-pyridine The method of example 1 was repeated, but starting with 20 140 g (0.4 mol) of 1,3-dihydro-3-£-f1uorophenyl-6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine. Yield 85 g (51 %) of a product melting at 198°C (Tottoli), with decomposition, the • analysis of which showed a good correspondence with the formula clgH21FN203.2HC1. 25 Example 8 lj 3-dihydro-3-p-tolyl -6-(l-hydroxy-2-d imethylaminomethyl-allyl) -7-hydroxy-furo-(3,4-c)-pyridine The method of example 1 was repeated, but starting with 138 g (0.4 mol) of 1,3-dihydro-3-p- tolyl -6-formyl-7-benzyloxy 30 -furo-(3,4-c)-pyr idine. Yield 81 g (49 %) of a product melting at 203-207°C (Tottoli), with decomposition, the analysis of which showed a good correspondence with the - 8 - formula C20H24N2°3. 2HC1.

Example 9 1,3-dihydro-3-p-methoxypheny1-6-(l-hydroxy-2-d imethylaminomethyl-allyl) -7-hydroxy-furo-(3,4-c)-pyr id ine 5 The method of example 1 was repeated, but starting with 145 g (0.4 mol) of 1,3-dihydro-3-p-methoxyphenyl-6- formyl-7-benzyloxy-furo-(3,4-c)-pyridine. Yield 86 g (50 %) of a product melting at 169-170°C (Tottoli), the analysis of which showed a good correspondence with the formula 10 ConH...N„0.. 2HC1. 20 24 2 4 Example 10 1,3-dihydro-3-m-tr ifluoromethylphenyl-6-(1-hydroxy-2-dimethyl-aminomethyl-allyl)-7-hydroxy-furo-[3,4-c)-pyr id ine The method of example 1 was repeated, but starting with 15 161 g (0.4 mol) of 1,3-dihydro-3-m-trifluoromethylpheny1-6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine. Yield 102 g (54 %) of a product melting at 217-223°C (Tottoli), with decomposition, the analysis of which showed a good correspondence with the formula C20H21F3N2°3* 2HC1. 20 Example 11 1,3-dihydro-3-p-(diethylaminoethoxy-pheny1)-6-(1-hydroxy-2-dimethylaminomethyl-allyl)-7-hydroxy-furo-(3j4-c)-pyr id ine The method of example 1 was repeated, but starting with 178 g (0.4 mol) of 1, 3-d ihydro-3-(p-diethyl aminoethoxy -phenyl) 25 -6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine. Yield 76 g (37 %) of a product melting at 158-160°C (Tottoli), the analysis of which showed a good correspondence with the formula C_CH N_0.. 2HC1. 25 35 3 4 - 9 - Example 12 1,3-dihydro-3-|p-||i-{N-pyrrolidinyl )-ethox£3-phenyl II - Antagonism against catalepsy induced by haloperidol 15 This experiment was conducted in comparison with two reference compounds, Imipramine and 5-hydroxytrytophane on male Wistar rats of 140/170 g in batches of each 6 rats.

IP administration of haloperidol at 5 mg/kg induces catalepsy. Further oral administration of the tested compounds 20 one hour after haloperidol injection has an adverse action against catalepsy.

Eight of the compounds of the invention were tested at various doses (one batch for each dose of each compound). Action on catalepsy was appreciated 1,2,3,4 and 5 hours after 25 the administration of the tested compounds by placing anterior paws of the rats on a metal bar located at 10 cm above table level (test performed in a noiseless room at 22°C) ; if the rat was able to stay for 20 seconds, the score was 1 point ; for 40 seconds the score was 2 points and so on up to 100 30 seconds for 5 points. Average values were calculated for each -13- batch together with the corresponding percentage of antagonism.

The results are reported in the table No. II.

Ill - Despair test on mice 5 This experiment was conducted on male mice CD-I (Charles River) in batches of each 10 mice in comparison with Maprotiline as a reference compound. One hour before the test, the mice received in a dose of 0.4 ml/20g of suspension, the appropriate dose in mg/kg of the tested compounds. 10 The mice were placed in plexiglass cylinder (height 25 cm, diameter 10 cm) containing water at 22°C. The measure of immobility period was effected between the 2nd and 6th minute. There was one control batch for each compound and one batch per tested dose. 15 The results are reported in the table No. Ill wherein A stands for the average immobility period and B stands for the % of variation with regard to control.

PRESENTATION - POSOLOGY More commonly used forms in human therapy comprise 20 tablets or gelatine capsules containing 0.1 g of active ingredient per dosage unit or phials containing the same amount in a dissolved or suspended form for IV injection.

Usual posology is up to 0.5 g/day for at least two weeks, for oral forms or up to 0.2 g/day for at least one 25 week for the injectable form, this treatment being followed by at least one week of oral administration. - 14 - Table No. I Products Doses L Yohimbine HC1 30 mg/kg SC 20 % Ex. 1 30 mg/kg PO 40 % 100 mg/kg PO 60 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 4 30 mg/kg PO 50 % 60 mg/kg PO 60 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 5 10 mg/kg PO 60 % 30 mg/kg PO 60 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 7 3 mg/kg PO 50 % 10 mg/kg PO 50 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 11 30 mg/kg PO 30 % 100 mg/kg PO 90 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 12 30 mg/kg PO 40 % 60 mg/kg PO 50 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 17 30 mg/kg PO 80 % 100 mg/kg PO 90 % Yohimbine HC1 30 mg/kg SC 20 % Ex. 20 30 mg/kg PO 50 % 100 mg/kg PO 60 % - 15 - Table No. II Examples Dose mg/kg per os Antagonism in % after : (hours) 1 h 2 h 3 h 4 h 5 h Imipramine 15 60 100 68.7 52.3 76.1 42.3 42.3 48.2 31 50 33.3 5 HTP 30 100 53.3 33.3 42.8 46.4 20.6 31 13.8 13.8 ' 16.6 16.6 Ex. 1 30 100 60 100 63.6 50 44 54.5 35.7 46.4 25 40 Ex. 4 1 3 58.3 100 70 75 50 80 33.7 56.6 16.6 50 Ex. 5 10 30 100 37 100 75 78 46 78 50 64 47 Ex. 7 3 10 0 28.5 58.3 79.1 60.7 78.6 41.4 79.3 48.2 72.4 Ex. 11 10 30 50 100 100 80.7 60 62.9 53.3 55.1 53.3 41.4 Ex. 12 10 30 0 0 30.4 30.4 37 40.7 43.3 46.6 46.6 40 Ex. 17 3 10 100 100 54.5 59 48.3 51.7 24.1 24.1 26.6 40 Ex. 20 10 30 93.3 100 76 68 70 50 60.7 54.5 55.1 51.7 - 16 - Table No. Ill Examples Doses A B Control - 204 Maprotiline 10 mg/kg PO 156.3 - 23.4 30 mg/kg PO 143.3 - 29.7 100 mg/kg PO 86.5 - 57.6 Control - 203.8 Ex. 1 1 mg/kg PO 157.4 - 25 3 mg/kg PO 133.1 - 34.7 10 mg/kg PO 82.1 - 59.6 Control - 198.3 Ex. 4 10 mg/kg PO 136.4 - 31.2 30 mg/kg PO 135.6 - 31.6 100 mg/kg PO 138.3 - 30.3 Control - 207.1 Ex. 5 10 fug/kg PO 145.4 - 29.8 30 mg/kg PO 124.4 - 39.9 100 mg/kg PO j 86.7 - 58.1 Control - 189.9 Ex. 7 3 mg/kg PO 137 - 27.9 10 mg/kg PO 135.2 - 28.8 30 mg/kg PO 101.1 - 46.6 Control - 200.3 Ex. 11 10 mg/kg PO 144.6 - 27.8 30 mg/kg PO 136.6 - 31.8 100 mg/kg PO 118.1 - 41.4 Control - 148.5 Ex. 12 30 mg/kg PO 106.1 - 28.6 100 mg/kg PO 99.0 - 33.3 300 mg/kg PO 77.4 - 47.9 Control - 200 Ex. 17 10 mg/kg PO 175.2 - 12.4 30 mg/kg PO 142.7 - 28.6 100 mg/kg PO 155.4 - 22.3 Control - 213.5 Ex. 20 10 mg/kg PO 183.4 - 14.1 30 mg/kg PO 86.3 - 59.6 60 mg/kg PO 97.2 - 54.5 - 17 -

Claims

1. A l,3-dihydro-6-(l-hydroxy-2-dimethylaminmoethyl-allyl)-7-hydroxy-5 -furo-(3,4-c)-pyridine derivative having the general formula I as defined herein or a pharmaceutically acceptable salt thereof.

2. l(3-dihydro-3-methyl-6-(l-hydroxy-2-dimethylaminomethyl-allyl)-7--hydroxy-furo-(3,4-c)-pyridine. 10

3. l,3-dihydro-3-propyl-6-(l-hydroxy-2-dimethylaminomethyl-allyl)-7--hydroxy-furo-(3,4-c)-pyridine.

4. l,3-dihydro-3-cyclohexyl-6-(l-hydroxy-2-dimethylaminomethyl-ally)-7-15 -hydroxy-furo-(3,4-c)-pyridine.

5. 1,3-dihydro-3-phenyl-6-(l-hydroxy-2-dimethylaminomethyl-ally)-7--hydroxy-furo-(3,4-c)-pyridine. 20

6. 1,3-dihydro-3-p-chlorophenyl-6-(l-hydroxy-2-dimethy1anrinoniethyl-ally) -7-hydroxy-furo-(3,4-c)-pyridine.

7. l,3-dihydro-3-(2l3-dichlorophenyl)-6-(l-hydroxy-2-dimethylaminomethyl -ally)-7-hydroxy-furo-(3,4-c)-pyridine. 25

8. 1,3-dihydro-3-p-fluorophenyl-6-(l-hydroxy-2-dimethylaminomethyl-ally) -7-hydroxy-furo-(3,4-c)-pyridine.

9. 1,3-dihydro-3-p-tolyl-6-(l-hydroxy-2-dimethylaminomethyl-ally)-7-30 -hydroxy-furo-(3,4-c)-pyri d i ne.

10. 1,3-d i hydro-3-p-methoxyphenyl-6-(l-hydroxy-2-dimethy1 ami nomethy1--allyl)-7-hydroxy-furo-(3,4-c)-pyridine. 35

11. 1,3-dihydro-3-m-trifluoromethylphenyl-6-(l-hydroxy-2-dimethylamino-methyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine. -18-

12. 1,3-dihydro-3-(p-diethylanrinoethoxy-phenyl)-6-(l-hydroxy-2-dimethyl-am i nomethy1-a11y1)-7-hydroxy-furo-(3,4-c)-pyr i d i ne.

13. 1,3-dihydro-3-{p-|$-(N-pyrrolidinyl)-ethoxy]-phenyl}-6-(l-hydroxy-5 -2-dimethylaminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine.

14. 1,3-di hydro-3-methy1-3-n-penty1-6-(l-hydroxy-2-dimethy1ami nomethy1--allyl)-7-hydroxy-furo-(3,4-c)-pyridine. 10

15. 1,3-dihydro-3-methyl-3-phenyl-6-(l-hydroxy-2-dimethylaminomethyl--allyl)-7-hydroxy-furo-(3,4-c)-pyridine.

16. 1,3-dihydro-3-methyl-3-«*w-thienyl-6-(l-hydroxy-2-dimethylaminomethyl--allyl)-7-hydroxy-furo-(3,4-c)-pyridine. 15

17. l,3-dihydro-3-ethyl-3-m-trifluoromethylphenyl-6-(l-hydroxy-2--d imethy1ami nomethy1-a11y1)-7-hydroxy-furo-(3,4-c)-pyr i d i ne.

18. l,3-dihydro-3-ethyl-3-«<-furyl-6-(l-hydroxy-2-dimethylaminomethyl-20 -allyl)-7-hydroxy-furo-(3,4-c)-pyridine.

19. 1,3-dihydro-3-phenyl-3-p-ethoxyphenyl-6-(l-hydroxy-2-dimethylamino-methyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine. 25

20. 1,3-dihydro-3,3-di-p-fluorophenyl-6-(l-hydroxy-2-dimethylamino-methyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine.

21. l,3-dihydro-3-o(-furyl-3-p-methylthiophenyl-6-(l-hydroxy-2-dimethyl-aminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine. 30

22. A process for the preparation of a 1,3-dihydro-6-(l-hydroxy-2-dimethylaminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine derivative having the general formula I as defined herein, the process comprising reacting a 6-formyl-7-benzyloxy-furo-(3,4-c)-pyridine derivative having 35 the general formula II as defined herein with 1-dimethylaminomethyl-vinylmagnesium bromide at the boil in a non-polar solvent and hydrolysing the 7-benzyloxy group of the resultant intermediate by treatment with an acid. -19-

23. A process according to claim 22 in which the non-polar solvent is tetrahydrofuran. 5

24. A process for the preparation of a 1,3-dihydro-6-(l-hydroxy-2- -dimethylaminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine derivative having the general formula I as defined herein, the process being substantially as described herein with reference to any of the Examples. 10

25. A pharmaceutical composition comprising a 1,3-dihydro-6-(l--hydroxy-2-dimethylaminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-pyridine derivative having the general formula I as defined herein or a pharmaceutically acceptable salt thereof in admixture with a 15 pharmaceutically acceptable diluent or carrier.

26. A l,3-dihydro-6-(l-hydroxy-2-dimethylaminomethyl-allyl)-7--hydroxy-furo-(3,4-c)-pyridine derivative whenever prepared by a process as claimed in any of claims 22, 23 or 24. 20 Dated this 1st day of February 1985. BY: TOMKINS & CO., 25 Applicants Agents' (Signed) 5, Dartmouth Road, DUBLIN 6. 30 35 -20-